Anastrozole is just as effective and may have fewer side-effects than tamoxifen in first-line treatment of advanced postmenopausal breast cancer

TRFATMFNTIINTFRVFNTION

Anastrozole is just as effective and may have fewer side-effects than tamoxifen in first-line treatment of advanced postmenopausal breast cancer Bonneterre J, Thurlimann B, Robertson JFR, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M, von Euler M. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen o r arimidex randomised group efficacy and tolerability study. J Clin Oncol 2000: 18: 3748-3757.

QUESTION Since advanced breast cancer is incurable, treatment focuses on palliation and slowing progression. Tamoxifen is an endocrine therapy, whch blocks estrogen receptors in hormone-sensitive tumors. It is accepted as the gold standard treatment due to its efficacy and fewer side-effects than other options. Anastrozole is often used as a second-line therapy. Compared to tamoxifen, what is the efficacy and tolerability of anastrozole as a first-line therapy for advanced postmenopausal breast cancer? DESIGN trial.

Randomized

double-blind multicenter

SETTING Eighty-three centres in Australia, Europe, New Zealand, South Africa and South America; recruitment August 1995-July 1998. PATIENTS Six hundred and sixtyeight postmenopausal women with locally advanced or metastatic breast cancer eligible for endocrine therapy, with hormone receptive tumors or unknown receptor status. Women with extensive visceral disease; previous systemic therapy for advanced breast cancer; concurrent illnesses whch could compromise the trial;

or who received tamoxifen in the year prior to the trial were ineligble.

INTERVENTIONS One milligram anastrozole or 20 mg tamoxifen daily. Patients ingested one active and one placebo tablet at approximately the same time each day. Treatment continued until disease progression. Median follow-up was 19 months. MAIN OUTCOME MEASURES Time to progression; objective tumor response to treatment (measured based on International Union Against Cancer tumor response criteria after 4 weeks and at all subsequent visits); tolerability. MAIN RESULTS There was no difference in median time to progression (8.2 months for anastrozole vs 8.3 months for tamoxifen) or objective response rate (32.9% anastrozole and 32.6% tamoxifen had complete or partial response) (see Table 1). Both treatments were well tolerated, with less vaginal bleeding and fewer thromboeinbolic events reported for the anastrozole group (see Table 2). Survival data analysis is not reported.

Evidence Table I. Response and disease free progression foranastrozole and tamoxifen in the treatment of advanced postmenopausal breast cancer

Objective tumor response Clinical benefit from therapy Progression Median time t o progression

% Tamoxifen ( n = 328)

% Anastrozole ( n = 340)

32.6 55.5 42. I 8.3 months

32.9 56.2 41.2 8.2 months

P-value

% Absolute risk change anastrozole vs tamoxifen

Relative risk anastrozole vs tamoxifen

>0.05 >0.05 >0.05 >0.05

0 ( - 7 t o 7) benefit I ( - 7 t o 8) benefit I ( - 7 t o 8) N o t calculable

I (0.8 t o 1.2) I (0.9 t o 1.2) I (0.8 t o 1.2) N o t calculable

Note: 95% confidence intervals in parentheses. Objective tumor response combines complete and partial responses (as described in abstract text). Negative figures show that tamoxifen may have more effect. Survival and disease-free progression after different time periods are not calculable from information provided in the article. Survival data are not analysed in this article and no subgroup analysis is undertaken. Numbers needed t o treat in order t o benefit one person have not been calculated since results are not statistically significant.

0 ZOO/Harcourt Publishers Ltd doi: 10. I054/ebon.2001.0099, available online at http://www.idealibrary.com on

lnEbl@

Evidence-based Oncology (200 I) 2, 73-76

Evidence Table 2. Incidence of adverse effects during daily anastrozole or tamoxifen treatment of advanced breast cancer in postmenopausal women

% Tamoxifen ( n = 329)

Vaginal bleeding Thromboembolic events Depression Nausea, vomiting o r diarrhoea H o t flushes Vaginal dryness Lethargy Weight gain

% Anastrozole ( n = 336) P-value

2.4

I .2

< 0.05

7.3 5.5

4.8 4.2

>0.05

28 20.7 I .8 2.7 I .8

23.5 20.5 2. I I .2 I .8

>0.05 >0.05 > 0.05 > 0.05 > 0.05

<0.05

Number of people needed to treat with tamoxifen to harm one person

%Absolute harm reduction from Relative risk anastrozole anastrozole vs vs tamoxifen tamoxifen

I (- I t o 3)

0.5 (0 t o 1.7)

40 ( I 6 t o - 89)* N o t statistically significant

3 ( - 1 to6) I (-2t05)

0.6 (0.04 t o 1.3) 0.8 (0.08 t o 1.4)

Not Not Not Not Not

4 ( - 2 to I I) O(-2to2) O(-2to2) 2 (- I t o 4) O(-2to2)

0.8 (0.6 t o I. I ) I (0.01 t o 2) I. I (0.06 t o 2.2) 0.4 (0 t o 1.6) I (0 t o 2.1)

83 (31 t o

-

statistically statistically statistically statistically statistically

122)*

significant significant significant significant significant

Note:95% confidence intervals in parentheses. I65 deaths were recorded, I3 during the treatment period.Analysis of survival data is not presented in the article. Effects are not necessarily linked t o treatment. Numbers needed t o treat in orderto harm one person have not been calculated for non-statistically significant results. *Vaginal bleeding and thromboembolic events are identified as significant in the article text. The derived ‘number needed t o treat’ and risk figures suggest non-significance but this may be due t o rounding error in the estimates used.

CONCLUSION Anastrozole is equivalent to tamoxifen in reducing disease progression and gaining a response for postmenopausal advanced receptorpositive breast cancer tumors. The reduced incidence of adverse effects suggests that anastrozole could be considered as a first-line therapy.

Sources dyunding: AstraZeneca,‘ U Corre~pondenceto: Jacques Bonneterre MD, PhD; Centre Oscar Lambret, 3 Rue Frederik Combemale, BP 307 Libe, France iemai~~-bonneterre@o-lambertfr.

Anastrozole is at least as effective as tamoxifen in first-line treatment of advanced postmenopausal breast cancer Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior t o tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicentre randomized trial. J Clin Oncol 2000; 18: 3758-3767.

QUESTION Tamoxifen is the gold standard endocrine treatment for advanced postmenopausal breast cancer but does not maximize the suppression of estrogen effects. Anastrozole is a relatively new aromatase inhbitor demonstrating greater estrogen suppression withn tumors, and peripherally. Compared to tamoxifen, what is the efficacy and tolerability of first-line anastrozole treatment for advanced breast cancer in postmenopausal women? DESIGN trial.

Randomized

double-blind multicenter

Evidence-based Oncology (200 I) 2,73-76

SETTING Ninety-seven centres in the United States and Canada; recruitment February 1996-July 1998. PATIENTS Three hundred and fifty-seven postmenopausal women with locally advanced or metastatic breast cancer eligible for endocrine therapy, with hormone receptive tumors or unknown receptor status. Women with extensive visceral disease; life expectancy less than 3 months; previous systemic therapy for advanced breast cancer; concurrent illnesses whch could compromise the trial; or who received tamoxifen in the year prior to the trial were ineligble. 0 ZOO/Harcoun Publishers Ltd

Evidence Table I. Response and disease free progression foranastrozoleand tamoxifen in the treatment of advanced postmenopausal breast cancer

% Tamoxifen ( n = 182)

% Absolute increase of benefit anastrozole vs tamoxifen

Relative risk anastrozole vs tamoxifen

17

21.1

>0.05

N o t statistically significant

4 ( - 4 t o 12)

I .2 (0.8 t o I .7)

45.6 52.2

59. I 36.8

<0.05 <0.05

7 (4 t o 32) 6 (4 t o 190)

14 (3 t o 24) 15 (5 t o 26)

1.3 ( 1 . 1 t o 1.5) 0.7 (0.5 t o I )

5.6 months

I I. I months

<0.05

N o t calculable

N o t calculable

N o t calculable

14.5 months

16.5 months

<0.05

N o t calculable

N o t calculable

N o t calculable

Objective response Clinical benefit from therapy Progression Median time t o progression Median duration of clinical benefit

% Anastrozole (n= I 7I) P-value

Number of people needed to treat in order to benefit one with anastrozole

Note: 95% confidence intervals in parentheses. Objective response combines complete and partial tumor responses as described in abstract text. Negative figures show that tamoxifen may have more effect. Survival and disease free progression after different time periods are not calculable from information provided in the article. Analysis of survival data is not presented in the article.

Evidence Table 2. Adverse effects incidence with daily anastrozole and tamoxifen treatment of advanced breast cancer in postmenopausal women

Vaginal bleeding Thromboembolic events Depression Tumor flare Nausea, vomiting o r diarrhoea H o t flushes Vaginal dryness Lethargy Weight gain

Number of people needed to treat with tarnoxifen to harm one person

% Tamoxifen ( n = 182)

% Anastrozole ( n = 170)

P-value

3.8

I .2

< 0.05

38 (17to -160)"

8.2 7.7 5.5

4. I 5.3 4. I

< 0.05 > 0.05 > 0.05

24(11 t o -114)" N o t statistically significant N o t statistically significant

57. I 27.5 3.8 3.3 1.1

53.5 38.2 4.7 I .2 2.9

> 0.05

N o t statistically -9 (-5 t o N o t statistically N o t statistically N o t statistically

<0.05 > 0.05 > 0.05 > 0.05

significant - 107) significant significant significant

% Absolute risk reduction with anastrozole

Relative risk anastrozole vs tamoxifen

t o 6)

0.3 (0 t o 1.9)

4 ( - I t o 9) 2 ( - 3 t o 8) I ( - 3 t o 6)

0.5 (0 t o 1.4) 0.7 (0 t o 1.5) 0.8 (0 t o 1.7)

3 (-I

4 ( - 7 t o 14) . I I ( - I t o -20) - I ( - 5 t o 3) 2 ( - I t o 5) -2 ( - 5 t o I )

0.9 1.4 1.2 0.4 2.7

(0.8 t o I. I ) ( 1 . 1 t o 1.7) (0.2 t o 2.2) (0 t o 1.9) ( I. I t o 4.3)

Note: 95% confidence intervals in parentheses. Negative figures show that anastrozole may have more adverse effects. Analysis of survival data is not presented in the article. Adverse effects listed are predefined rather than necessarily relating t o treatment. N o deaths related t o study treatment are reported. *Vaginal bleeding and thromboembolic events are suggested as significantly different between groups in the article text. The derived 'number needed t o treat' and risk figures suggest non-significance but this may be due t o rounding error in the estimates used.

INTERVENTIONS One milligram anastrozole or 20 mg tamoxifen daily. Patients ingested two tablets (one active and one placebo) at similar times daily. Treatment continued until disease progression. Follow-up occurred until objective progression and death. Median follow-up was 17.7 months. Details of blinding not provided in article. MAIN OUTCOME MEASURES Complete or partial objective tumor response (measured based on International Union Against Cancer tumor response 0 ZOO/Harcourt Publishers Ltd

criteria after 4 weeks and at all subsequent visits); time to progression; tolerability.

MAIN RESULTS There was no difference in objective response among the anastrozole and tamoxifen groups (21 vs 17%, respectively). Anastrozole showed enhanced clinical benefit and decreased median time to progression (see Table 1). Tolerability was good in both groups, with reduced vaginal bleeding and thromboembolic events in those who received anastrozole (see Table 2). Evidence-based Oncology (200 I) 2, 73-76

offunding: AstraZeneca

CONCLUSION Anastrozole could be considered as a first-line treatment for advanced postmenopausal breast cancer. It is equivalent to tamoxifen in terms of objective response; increases median time to progression; and reduces some side-effects. Clinical benefit is increased but the study was not initially designed to test for this factor.

Sources

Commentary

The TARGET study and the North American trial do demonstrate that short-term administration of anastrozole is equivalent t o tamoxifen in postmenopausal women with advanced breast cancer. In addition, anastrozole’s relatively better tolerability profile is likely t o be substantiated. The assertion, however, that anastrozole is superior t o tamoxifen may remain a contentious issue even after final analyses of these data are complete. Until there are unequivocal data demonstrating that outcomes from anastrozole therapy have surpassed the recognized benefits of tamoxifen in women with hormone-dependent breast cancer, regardless of menopausal status o r risk o r stage of the disease, claims of superiorityare premature.

Tamoxifen has been long established as the endocrine therapy of choice in postmenopausal women with advanced hormone-dependent breast cancer. While the tolerability profile of tamoxifen was the primary basis for this distinction, it has, paradoxically, also stimulated a resurgence of interest aimed at antagonizing estrogenic action with less toxicity. A primary target is the enzyme aromatase, which catalyzes the conversion of androgens t o estrogens. Strategically positioned in the estrogen biosynthetic pathway, inhibition of aromatase can be selective and relatively specific. Expressed in extra-ovarian tissue, aromatase can contribute t o high local production of hormones in the breast, leading t o the intriguing speculation that deregulation of aromatase may be a malefic conduit between estrogens and breast cancer.’-3 Both the larger TARGET study and the smaller N o r t h American trial report equivalence of anastrozole t o tamoxifen. The results, while not totally unexpected, provide further evidence that estrogen deprivation is the operative mode of all endocrine therapies. However, this mechanism alone does n o t explain anastrozole’s time t o progression advantage reported by the North American investigators. Analyses of the combined data set may nullitj this finding, since the hormone receptor status of a large percentage of patients in the TARGET study was not known. While response rate and response duration are important end-points, palliation of symptoms and patient well-being are equally relevant in oncology. The greater number of embolic events in the tamoxifen arm is consistent with previous studies of this agent:,’ However, the surprisingly high incidence in bath arms suggests increased age and advanced disease may independently augment the risk of thrombotic complications. Although there is a striking parallel in nearly all reported adverse events, the relative variance in vaginal bleeding and asthenia between treatment arms is of special interest. Both of these symptoms have been reported t o be among the most distressing side-effects impelling patients t o request a change of treatment! Thus, when the combined study data are analyzed, persistence of small absolute differences (even in the absence of being statistically significant) in these and other outcomes assessed could be magnified by the thousands ofwomen who will be prescribed these agents.

Evidence-based Oncology (200 I) 2,73-76

Correqondence to: JM Nabholq M D MS6 Universig of Calfornia at L o s Angeles, Peter Ueberroth Buildin& Number 3360B 10945 Leconte Ave, L o s Angeles C4 90095-7077 (emai~~ean-marc.nabhol~ bcirgmm).

Ranking criteria for articles: relevance: 4, validity: 3, applicability: 4, feasibility: 4, impact: 3, knowledge context: 4.

Gerald M. Higa, PharmD West Virginia University, Morgantown, WV, USA Literature cited I. Siegelmann-Daniel1 N, Zhang JQ, McGlynn KA, Buetow KH. DNA-based variation at the aromatase gene (CYP 19) and its role in breast cancer susceptibility [abstr]. Proc A m Assoc Cancer Res 1996; 15: 2004a. 2. Miller WR. Aromatase activity in breast tissue. J Steroid Biochem Mol Biol I99 I; 39: 783-790. 3. Durgam VR, Tekmal RR. The nature and expression of int-5, a novel MMTV integration locus gene in carcinogen-induced tumors. Cancer Lett 1994; 8 7 179-86. 4. Fisher B, Costantino JP. Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-I study. J Natl Cancer lnst 1998; 90: 1371-1388. 5. Fisher B, Dignam J, Bryant J et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer lnst 1996; 88: 1529-1 542. 6. Leonard RCF, Lee L, Harrison ME. Impact of side-effects associated with endocrine treatments for advanced breast cancer: clinicians’ and patients’ perceptions. The Breast 1996; 5: 259-264. Level and quality of evidence (see Table A): I c

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